Male and female mice develop escalation of heroin intake and dependence following extended access

Towers, Eleanor Blair; Tunstall, Brendan J.; McCracken, Mandy L.; Vendruscolo, Leandro F.; Koob, George F.

doi:10.1016/j.neuropharm.2019.03.019

Cited by 60 publications

(56 citation statements)

References 37 publications

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“…The LgA mice were allowed to self-administer fentanyl vapor continuously for 12 hours. Consistent with previous studies (9,49) and based on pilot experiments in female mice that showed increased fentanyl vapor intake during the first 12-hour escalation session compared with male mice ( fig. S7), female mice in the LgA-Fen group underwent three LgA sessions in which the number of vapor deliveries was capped before their escalation phase (two sessions capped at 30 vapor deliveries and one session capped at 60 vapor deliveries).…”

Section: Escalation Of Fentanyl Vapor Self-administrationsupporting

confidence: 91%

“…They were then placed in clear Plexiglas boxes (20 cm × 20 cm × 29 cm) and video-recorded for 20 min. The videos were scored by two observers (one of them blinded to experimental group) as previously described ( 9 ) to generate a total score of naloxone-precipitated somatic signs of withdrawal. Briefly, the withdrawal signs included jumps, paw tremor (clapping behavior), and wet dog shakes, which were weighted equally and given one point for each occurrence.…”

Section: Methodsmentioning

confidence: 99%

“…Mouse models offer unique advantages compared with rats in neurobiological investigations when considering the numerous behaviorally selected and transgenic mouse strains that allow genetic targeting and manipulation using sophisticated techniques (e.g., imaging, chemogenetics, and optogenetics). Although intravenous self-administration models in mice have been used successfully (8,9), the use of such models in opioid addiction research remains very scarce and restricts the duration of exposure to drugs because of high catheter failure rates, especially during prolonged access to drugs (8,10). Intravenous catheters also limit the ability to perform in vivo electrophysiology or calcium imaging experiments in freely moving mice, in part, because of double tethering.…”

Section: Introductionmentioning

confidence: 99%

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Fentanyl vapor self-administration model in mice to study opioid addiction

et al. 2020

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Intravenous drug self-administration is considered the “gold standard” model to investigate the neurobiology of drug addiction in rodents. However, its use in mice is limited by frequent complications of intravenous catheterization. Given the many advantages of using mice in biomedical research, we developed a noninvasive mouse model of opioid self-administration using vaporized fentanyl. Mice readily self-administered fentanyl vapor, titrated their drug intake, and exhibited addiction-like behaviors, including escalation of drug intake, somatic signs of withdrawal, drug intake despite punishment, and reinstatement of drug seeking. Electrophysiological recordings from ventral tegmental area dopamine neurons showed a lower amplitude of GABAB receptor–dependent currents during protracted abstinence from fentanyl vapor self-administration. This mouse model of fentanyl self-administration recapitulates key features of opioid addiction, overcomes limitations of the intravenous model, and allows investigation of the neurobiology of opioid addiction in unprecedented ways.

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Section: Escalation Of Fentanyl Vapor Self-administrationsupporting

confidence: 91%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Fentanyl vapor self-administration model in mice to study opioid addiction

et al. 2020

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“…The present results are consistent with previous opioid escalation studies in male rats (31). However, the present results are in contrast to reports of female rodents showing greater rates of opioid escalation than males (24,(32)(33)(34) in some studies, but not all (35)(36)(37). Reasons for inconsistent sex differences in rates of opioid self-administration are not presently clear and could reflect differences in either the self-administered opioid or other experimental conditions.…”

Section: Discussionsupporting

confidence: 91%

Opioid withdrawal produces sex-specific effects on fentanyl-vs.-food choice and mesolimbic transcription

Townsend

Kim

Marsh

et al. 2021

Preprint

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BackgroundOpioid withdrawal is a key driver of opioid addiction and an obstacle to recovery. However, withdrawal effects on opioid reinforcement and mesolimbic neuroadaptation are understudied and the role of sex is largely unknown.MethodsMale (n=10) and female (n=9) rats responded under a fentanyl-vs.-food “choice” procedure during daily 2h sessions. In addition to the daily choice sessions, rats were provided extended access to fentanyl during 12h sessions. After two weeks of this self-administration regimen, the nucleus accumbens (NAc) and ventral tegmental area (VTA) of a subset of rats were subjected to RNA sequencing. In the remaining rats, a third week of this self-administration regimen was conducted, during which methadone effects on fentanyl-vs.-food choice were determined.ResultsPrior to opioid dependence, male and female rats similarly allocated responding between fentanyl and food. Abstinence from extended fentanyl access elicited a similar increase in somatic withdrawal signs in both sexes. Despite similar withdrawal signs and extended access fentanyl intake, opioid withdrawal was accompanied by a maladaptive increase in fentanyl choice in males, but not females. Behavioral sex differences corresponded with transcriptional hyperfunction in the NAc and VTA of opioid-withdrawn females relative to males. Methadone blocked withdrawal-associated increases in fentanyl choice in males, but failed to further decrease fentanyl choice in females.ConclusionsThese results provide foundational evidence of sex-specific neuroadaptations to opioid withdrawal, which may be relevant to the female-specific resilience to withdrawal-associated increases in opioid choice and aid in the identification of novel therapeutic targets.

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“…In the studies described above, opioid self-administration session lengths are typically short (e.g., 2 h) in duration and daily opioid exposure is insufficient for rats to become opioid dependent as demonstrated by somatic withdrawal signs when opioid self-administration is terminated or an opioid antagonist is administered [48]. However, when access conditions are increased by prolonging opioid self-administration session duration (e.g., 12 h), rats will become opioid dependent as confirmed by somatic withdrawal signs following opioid antagonist administration [48][49][50][51]. Two studies have evaluated vaccine effects under these experimental conditions.…”

Section: Vaccine Effects On Maintenance Of Opioid Self-administrationmentioning

confidence: 99%

Preclinical Evaluation of Vaccines to Treat Opioid Use Disorders: How Close are We to a Clinically Viable Therapeutic?

Townsend¹,

Banks²

2020

CNS Drugs

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The ongoing opioid crisis, now into its second decade, represents a global public health challenge. Moreover, the opioid crisis has manifested despite clinical access to three approved opioid use disorder medications: the full opioid agonist methadone, the partial opioid agonist buprenorphine, and the opioid antagonist naltrexone. Although current opioid use disorder medications are underutilized, the ongoing opioid crisis has also identified the need for basic research to develop both safer and more effective opioid use disorder medications. Emerging preclinical evidence suggests that opioid-targeted vaccines or immunopharmacotherapies may be promising opioid use disorder therapeutics. One premise for this article is to critically examine whether vaccine effectiveness evaluated using preclinical antinociceptive endpoints is predictive of vaccine effectiveness on abuse-related endpoints such as drug self-administration, drug discrimination, and conditioned place preference. A second premise is to apply decades of knowledge in the preclinical evaluation of candidate small-molecule therapeutics for opioid use disorder to the preclinical evaluation of candidate opioid use disorder immunopharmacotherapies. We conclude with preclinical experimental design attributes to enhance preclinical-to-clinical translatability and potential future directions for immunopharmacotherapies to address the dynamic illicit opioid environment. Key Points Vaccine effectiveness should be assessed in terms of opioid agonist potency shifts. Vaccine effectiveness on a preclinical endpoint should be directly compared to effectiveness with naltrexone or buprenorphine treatment. Vaccine effectiveness should be evaluated on preclinical endpoints that are analogous to clinical opioid use disorder endpoints to enhance translational concordance.

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Male and female mice develop escalation of heroin intake and dependence following extended access

Cited by 60 publications

References 37 publications

Fentanyl vapor self-administration model in mice to study opioid addiction

Fentanyl vapor self-administration model in mice to study opioid addiction

Opioid withdrawal produces sex-specific effects on fentanyl-vs.-food choice and mesolimbic transcription

Preclinical Evaluation of Vaccines to Treat Opioid Use Disorders: How Close are We to a Clinically Viable Therapeutic?

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